SUMMARY Dynamics of interorgan communication and biological age change as a function of chronological age but these dynamics and the underlying mechanisms are not well understood. Organ transplantation offers a clinically most relevant model with donor/recipient age-discrepant combinations representing a clinical routine to meet the ever- increasing organ demands. Our published studies and preliminary data show that an elevated donor age drives the immunogenicity of organs leading to augmented alloimmune responses with higher acute rejection rates. This, in turn, is blunted with the increase of recipient age, demonstrating both clinical relevance and inter- organ/recipient communication. These clinically relevant scenarios raise the possibility of potential rejuvenation and/or accelerated aging when performing heterochronic organ transplants. We have shown that the recipient environment can affect the biological age of transplanted organs. Specifically, when transplanting old organs in young recipients, we observed the reduction of donor organ biological age. At the same time, old organs transplanted into young recipient mice promoted aging, which not only led to an accumulation of senescent cells in peripheral organs, but also to a decline of physical and cognitive functions. Our project brings together a synergistically positioned group of aging and transplantation researchers and clinicians. Vadim Gladyshev (MPI) is an expert on aging biomarkers and the biology of aging. Stefan Tullius (MPI) is a clinician/scientist who provides the clinical perspective. The latest generation of aging biomarkers based on omics approaches, combined with state-of-the-art model systems place us in an unprecedented position to study inter-organ dynamics of aging. Our hypothesis is that that young and old cells transferred with an organ transplant may exert rejuvenating and aging effects extrinsically. This hypothesis will be tested in our established transplant models of clinical relevance and confirmed using a unique clinical database. We also hypothesize that transplanted organs will acquire the biological age approaching that of recipients. This includes the situation wherein old donor organs will be rejuvenated in young recipients, potentially increasing the use of discarded organs. This approach is significant and innovative in (i) delineating novel mechanisms of interorgan communication in a clinically relevant heterochronic transplantation model with perturbation of specific tissues, (ii) the use of state-of-the-art tools of aging science to characterize changes in biological age dynamics, (iii) the use of detailed mechanistic approaches to pinpoint changes in interorgan communication upon biological age perturbation; (iv) synergistic efforts of research groups combining deep complementary expertise in preclinical and clinical studies of aging biology and transplant medicine; and (v) real-world implications of the proposed work. These studies position us to...